The proposed studies will use innovative approaches to expand the use of iPS to change treatment paradigms for NIDDK-related diseases. We therefore hypothesize that murine iPS cell derived mesenchymal stem cells and adipocytes offer the potential for cell-based therapy to treat lipodystrophy. We propose to create a set of mouse iPS cell models of lipodystrophy using transgene-free approaches for the purpose of evaluating the differentiation potential of young versus aged derived iPS relative to BM-MSC to mesenchymal and adipose lineages and subsequent function. We will also test the ability of the iPS cell derived mesenchymal stem cells to rescue a mouse model of lipodystrophy relative to BM-MSC. This model will enable us to identify a cell type which may be suited as a potential therapy. Additionally, these studies will generate important resources and reagents that will be of vast interest to both the scientific and medical communities. PUBLIC HEALTH RELEVANCE: Lipodystrophies are the result of adipose tissue degeneration as well as misdistribution and result in severe defects in lipid and glucose homeostasis. The therapeutic potential of iPS derived mesenchymal stem cells for tissue repair and regeneration is almost limitless with respect to lipodystrophy. These studies will enable the delivery of truly personalized medical treatment for lipodystrophy since the iPS cells would be eventually generated from the same individual in need of treatment.